The combined activity of four transcription factors (Oct4, Sox2, cMyc and Klf4) can reprogram adult cells into induced pluripotent stem (iPS) cells. These reprogrammed cells should provide a limitless supply of genetically tailored cell types for transplantation medicine, drug discovery and the study of human disease. Unfortunately, the methods used to deliver reprogramming factors have either raised concerns regarding the future utility of the resulting stem cells, or may not be compatible with industrial scale production of clinically compatible stem cell lines. Here, we propose to determine the mechanisms of action of small molecules that we have shown can facilitate the reprogramming process by either increasing its efficiency or by allowing the omission of one or more reprogramming factors. Our final goal is to move towards the identification of a chemical formulation that can alone reprogram adult cells to a pluripotent state. These reprogrammed cells would be free of genetic manipulation and would be the optimal pluripotent cells for biomedical applications. Specifically the aims are: aim 1) To determine the mechanisms by which newly identified small reprogramming molecules act to replace Klf4 in the reprogramming process; aim 2) To determine the mechanisms by which newly identified small reprogramming molecules that can replace Oct4 act in the reprogramming process; aim 3) To determine whether the reprogramming molecules that we have identified can act synergistically to replace multiple reprogramming transcription factors, thus moving us closer to a completely chemical method for reprogramming.